Patients with sickle cell disease experience a 400 fold increased risk of severe pneumococcal infection. This risk is not shared by other encapsulated pathogens or by other anemias suggesting that there is a potentially causal relationship between severity of pneumococcal disease and the SS phenotype. This application seeks to investigate two aspects of pneumococcal infection in sickle cell disease. Over the previous grant cycle, a collaboration between the program in pneumococcal pathogenesis and the SS transplant mouse model has revealed the PAF receptor to be a key determinant of increased invasive disease. Specific receptor antagonists improve the outcome of disease. This provides a model to examine the bacterial and host determinants of severe disease to be studied in the next grant period. Building on a strong history of this Center's study of the colonization of SS patients with antibiotic resistant pneumococci, the effect of the new seven-valent conjugate pneumococcal vaccine on nasopharyngeal carriage with specific reference to antibiotic susceptibility and shifts away from vaccine serotypes is being studied. These studies may also have implications for the efficacy of continued penicillin prophylaxis in this at risk population. All cohorts for the study have been fully enrolled and will now be followed for the next grant period. Investigation of the genomic content of strains collected thusfar using microarrays has indicated that SS pneumococci that become invasive carry a specific set of genes, most notably related to iron transport. This property will be examined in the entire clinical cohort of strains and the relationship of the function of the locus to pathogenesis will be determined by mutational analysis and phenotype in the mouse model established in the first grant cycle.